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Query: UMLS:C0011570 (depression)
 172,036 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Synaptic long-term potentiation (LTP) and long-term depression (LTD) were studied in the visual cortex of mutant mice lacking alpha-calcium/calmodulin-dependent protein kinase II (alphaCaMKII). In adult mutants, little LTD or LTP could be elicited using standard conditioning protocols. However, substantial LTD and LTP were induced in 4- to 5-week-old mutants. Thus, the reduction in cortical plasticity in alphaCaMKII (-/-) mice is conditional, with the relevant condition being postnatal age.
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PMID:Age-dependent decrease of synaptic plasticity in the neocortex of alphaCaMKII mutant mice. 909 2

Brief bath application of N-methyl-D-aspartate (NMDA) to hippocampal slices produces long-term synaptic depression (LTD) in CA1 that is (1) sensitive to postnatal age, (2) saturable, (3) induced postsynaptically, (4) reversible, and (5) not associated with a change in paired pulse facilitation. Chemically induced LTD (Chem-LTD) and homosynaptic LTD are mutually occluding, suggesting a common expression mechanism. Using phosphorylation site-specific antibodies, we found that induction of chem-LTD produces a persistent dephosphorylation of the GluR1 subunit of AMPA receptors at serine 845, a cAMP-dependent protein kinase (PKA) substrate, but not at serine 831, a substrate of protein kinase C (PKC) and calcium/calmodulin-dependent protein kinase II (CaMKII). These results suggest that dephosphorylation of AMPA receptors is an expression mechanism for LTD and indicate an unexpected role of PKA in the postsynaptic modulation of excitatory synaptic transmission.
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PMID:NMDA induces long-term synaptic depression and dephosphorylation of the GluR1 subunit of AMPA receptors in hippocampus. 985 70

Long-term depression has recently been shown to occur at glutamatergic synapses in the avian hippocampus and requires activation of calcium/calmodulin-dependent protein kinase II in the nerve terminal. Here using whole cell and intracellular recordings from brain slices, we show that the N-type calcium channel contributes significantly to glutamate release in the avian hippocampus. Activation of the metabotrobic gamma-aminobutyric acid (GABA)(B) receptor by the specific agonist baclofen blocks synaptic transmission. The action of baclofen was associated with a change in paired pulse facilitation indicating that it resulted from a reduction in the probability of transmitter release. In contrast, no change in paired pulse facilitation was observed following the induction of long-term depression. These results show that activation of GABA(B) receptors and long-term depression reduce transmitter release by distinct mechanisms.
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PMID:Inhibition of transmitter release and long-term depression in the avian hippocampus. 1077 Nov 51

Bidirectional changes in the efficacy of neuronal synaptic transmission, such as hippocampal long-term potentiation (LTP) and long-term depression (LTD), are thought to be mechanisms for information storage in the brain. LTP and LTD may be mediated by the modulation of AMPA (alpha-amino-3-hydroxy-5-methyl-4-isoxazloe proprionic acid) receptor phosphorylation. Here we show that LTP and LTD reversibly modify the phosphorylation of the AMPA receptor GluR1 subunit. However, contrary to the hypothesis that LTP and LTD are the functional inverse of each other, we find that they are associated with phosphorylation and dephosphorylation, respectively, of distinct GluR1 phosphorylation sites. Moreover, the site modulated depends on the stimulation history of the synapse. LTD induction in naive synapses dephosphorylates the major cyclic-AMP-dependent protein kinase (PKA) site, whereas in potentiated synapses the major calcium/calmodulin-dependent protein kinase II (CaMKII) site is dephosphorylated. Conversely, LTP induction in naive synapses and depressed synapses increases phosphorylation of the CaMKII site and the PKA site, respectively. LTP is differentially sensitive to CaMKII and PKA inhibitors depending on the history of the synapse. These results indicate that AMPA receptor phosphorylation is critical for synaptic plasticity, and that identical stimulation conditions recruit different signal-transduction pathways depending on synaptic history.
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PMID:Regulation of distinct AMPA receptor phosphorylation sites during bidirectional synaptic plasticity. 1087 37

Postsynaptic Ca2+ signals of different amplitudes and durations are able to induce either long-lasting potentiation (LPT) or depression (LTD). The bidirectional character of synaptic plasticity may result at least in part from an increased or decreased responsiveness of the glutamatergic alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid receptor (AMPA-R) due to the modification of conductance and/or channel number, and controlled by the balance between the activities of phosphorylation and dephosphorylation pathways. AMPA-R depression can be induced by a long-lived Ca2+ signal of moderate amplitude favouring the activation of the dephosphorylation pathway, whereas a shorter but higher Ca2+ signal would induce AMPA-R potentiation resulting from the preferential activation of the phosphorylation pathway. Within the framework of a model involving calcium/calmodulin-dependent protein kinase II (CaMKII), calcineurin (PP2B) and type 1 protein phosphatase (PP1), we aimed at delineating the conditions allowing a biphasic U-shaped relationship between AMPA-R and Ca2+ signal amplitude, and thus bidirectional plasticity. Our theoretical analysis shows that such a property may be observed if the phosphorylation pathway: (i) displays higher cooperativity in its Ca2+-dependence than the dephosphorylation pathway; (ii) displays a basal Ca2+-independent activity; or (iii) is directly inhibited by the dephosphorylation pathway. Because the experimentally observed inactivation of CaMKII by PP1 accounts for this latter characteristic, we aimed at verifying whether a realistic model using reported parameters values can simulate the induction of either LTP or LTD, depending on the time and amplitude characteristics of the Ca2+ signal. Our simulations demonstrate that the experimentally observed bidirectional nature of Ca2+-dependent synaptic plasticity could be the consequence of the PP1-mediated inactivation of CaMKII.
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PMID:Bidirectional synaptic plasticity as a consequence of interdependent Ca2+-controlled phosphorylation and dephosphorylation pathways. 1282 59

Neuronal synaptic connections can be potentiated or depressed by paired pre- and postsynaptic spikes, depending on the spike timing. We show that in cultured rat hippocampal neurons a calcium/calmodulin-dependent protein kinase II (CaMKII)-mediated potentiation process and a calcineurin-mediated depression process can be activated concomitantly by spike triplets or quadruplets. The integration of the two processes critically depends on their activation timing. Depression can cancel previously activated potentiation, whereas potentiation tends to override previously activated depression. The time window for potentiation to dominate is about 70 ms, beyond which the two processes cancel. These results indicate that the signaling machinery underlying spike timing-dependent plasticity (STDP) may be separated into functional modules that are sensitive to the spatiotemporal dynamics (rather than the amount) of calcium influx. The timing dependence of modular interaction provides a quantitative framework for understanding the temporal integration of STDP.
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PMID:Coactivation and timing-dependent integration of synaptic potentiation and depression. 1565 96

In searching for genes dysregulated in schizophrenia, we measured the expression of the two splice variants of calcium/calmodulin-dependent protein kinase II (CaMKIIalpha and CaMKIIbeta) in postmortem frontal cerebral cortex tissues from patients who had died with schizophrenia, bipolar disorder, or severe depression. The mRNA levels of expression of these two splice variants were measured by real-time Quantitative PCR, using an Mx4000 instrument. The values for the expression of CaMKIIalpha and CaMKIIbeta were normalized by the expression of beta-glucuronidase in the tissues. The expression of CaMKIIalpha was significantly elevated in the depression tissues by 29%. The expression of CaMKIIbeta was significantly elevated in the schizophrenia tissues by 27%, and in the depression tissues by 36%. Because CaMKIIbeta influences the expression of many neuroreceptors and influences neural outgrowth and pruning, its altered expression in the cerebral cortex in schizophrenia or depression may contribute to these diseases.
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PMID:Increased expression of calcium/calmodulin-dependent protein kinase IIbeta in frontal cortex in schizophrenia and depression. 1624 65

Activation of postsynaptic alpha-calcium/calmodulin-dependent protein kinase II (alphaCaMKII) by calcium influx is a prerequisite for the induction of long-term potentiation (LTP) at most excitatory synapses in the hippocampus and cortex. Here we show that postsynaptic LTP is unaffected at parallel fiber-Purkinje cell synapses in the cerebellum of alphaCaMKII(-/-) mice. In contrast, a long-term depression (LTD) protocol resulted in only transient depression in juvenile alphaCaMKII(-/-) mutants and in robust potentiation in adult mutants. This suggests that the function of alphaCaMKII in parallel fiber-Purkinje cell plasticity is opposite to its function at excitatory hippocampal and cortical synapses. Furthermore, alphaCaMKII(-/-) mice showed impaired gain-increase adaptation of both the vestibular ocular reflex and optokinetic reflex. Since Purkinje cells are the only cells in the cerebellum that express alphaCaMKII, our data suggest that an impairment of parallel fiber LTD, while leaving LTP intact, is sufficient to disrupt this form of cerebellar learning.
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PMID:alphaCaMKII Is essential for cerebellar LTD and motor learning. 1698 13

The hippocampus is a brain region critical for learning and memory processes believed to result from long-lasting changes in the function and structure of synapses. Recent findings suggest that ATP functions as a neurotransmitter or neuromodulator in the mammalian brain, where it activates several different types of ionotropic and G protein-coupled ATP receptors that transduce calcium signals. However, the roles of specific ATP receptors in synaptic plasticity have not been established. Here we show that mice lacking the P2X3 ATP receptor (P2X3KO mice) exhibit abnormalities in hippocampal synaptic plasticity that can be restored by pharmacological modification of calcium-sensitive kinase and phosphatase activities. Calcium imaging studies revealed an attenuated calcium response to ATP in hippocampal neurons from P2X3KO mice. Basal synaptic transmission, paired-pulse facilitation and long-term potentiation are normal at synapses in hippocampal slices from P2X3KO. However, long-term depression is severely impaired at CA1, CA3 and dentate gyrus synapses. Long-term depression can be partially rescued in slices treated with a protein phosphatase 1-2 A activator or by postsynaptic inhibition of calcium/calmodulin-dependent protein kinase II. Despite the deficit in hippocampal long-term depression, P2X3KO mice performed normally in water maze tests of spatial learning, suggesting that long-term depression is not critical for this type of hippocampus-dependent learning and memory.
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PMID:Impaired long-term depression in P2X3 deficient mice is not associated with a spatial learning deficit. 1707 61

Ageing is associated with a general decline in physiological functions. Amongst the different aspects of body deterioration, cognitive impairments, and particularly defects in learning and memory, represent one of the most frequent features in the elderly. However, a great variability exists among aged subjects. Clinical reports and experimental data in animal models of ageing have shown that age-associated memory deficits are broadly identical to those induced by damage to the hippocampus. It is therefore not surprising that many functional properties of hippocampal neuronal networks are particularly altered with ageing. Whereas passive membrane properties of neurons are conserved with age, neuronal excitability is altered, in keeping with weaker performances of aged subjects in memory tasks. Synaptic transmission within hippocampal networks also decreases in brain ageing. Deficits concern both glutamatergic and cholinergic pathways, which represent the main excitatory neurotransmitter systems responsible for neuronal communication in the hippocampus. In addition, long-term changes in synaptic transmission, possible cellular substrates for learning and memory, are also impaired in ageing in correlation with cognitive impairments. Neuronal properties and synaptic plasticity closely depend on ion exchanges between intra- and extracellular compartments. Changes in ion regulation during ageing may therefore participate in altering functional properties of neuronal networks. Calcium dysregulation has been extensively investigated in brain ageing but the role of magnesium has received less attention though ageing constitutes a risk factor for magnesium deficit. One of general properties of magnesium at presynaptic fibre terminals is to reduce transmitter release. At the postsynaptic level, it closely controls the activation of the N-methyl-D-aspartate receptor, a subtype of glutamate receptor, which is critical for the expression of long-term changes in synaptic transmission. In addition, magnesium is a cofactor of many enzymes localized either in neurons or in glial cells that control neuronal properties and synaptic plasticity such as protein-kinase C, calcium/calmodulin-dependent protein kinase II and serine racemase. It is therefore likely that a change in magnesium concentration would significantly impair synaptic functions in the aged hippocampus. Experiments addressing this question remain too scarce but recent data indicate that magnesium is involved in age-related deficits in transmitter release, neuronal excitability and in some forms of synaptic plasticity such as long-term depression of synaptic transmission. Further studies are still necessary to better delineate to what extent magnesium contributes to the impaired cellular mechanisms of cognitive functions in the elderly which will help to develop new strategies to minimize age-related memory declines.
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PMID:Ageing, hippocampal synaptic activity and magnesium. 1717 10


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